Free radicals and the peroxidative processes caused by them are believed to be one of the causes of the structural and functional degradations of human tissue during aging. It is important to maintain the concentration of natural antioxidant molecules (free radical scavengers) high inside and around the body's various tissues and cells including ocular tissues like the retina, vitreous and the crystalline lens, iris-ciliary body and trabecular meshwork, cornea and conjunctival tissues, and in the body's liquids including the aqueous humor of the anterior eye chamber and in the blood plasma and blood stream in order to supplement organs, tissues and cells and to prevent or minimize the aging processes and related (ocular) pathologies and for longevity. For example, it is believed that in some forms of cataract, especially those associated with retinal disorders, lens clouding is due to the diffusion of toxic products deriving from the oxidation of the lipids from the retina through the vitreous body to the lens. See Babizhayev et al., Biochimica et Biophysica Acta, 1004 (1989), 124-133 and references cited therein.
L-Carnosine (β-alanyl-L-histidine) and some derivatives thereof (acetylcarnosine, carcinine, anserine, acetylanserine, balenine, etc.) are known to be among the most important and potent natural antioxidant agents which act as universal antioxidants both in the lipid phase of cellular and biological membranes and in the aqueous environment protecting lipids and water-soluble molecules like proteins (including enzymes), DNA and other essential macromolecules from oxidative damage mediated by reactive oxygen species and lipid peroxides. Babizhayev et al., Biochem. J. 304 (1994), 509-516 and references cited therein; Babizhayev et al., Biochemistry (Moscow) 63 (1998), 523-528; and Babizhayev et al., Clinica Chimica Acta 254 (1996) 1-21.
A striking effect of L-carnosine was demonstrated and has been used in the preventive and therapeutical treatment of cataract. See Babizhayev, Biochimica and Biophysica Acta, 1004 (1989), 363-371; and Boldyrev et al., Biochem. Intern. 15, 1105-1113.
However, exogenous carnosine, even when topically administered to the eye, does not accumulate in tissues, but it is excreted with urine or it is preferably destroyed by the enzyme carnosinase, which is present in blood plasma, aqueous humor of the anterior eye chamber, liver and kidney and other tissues, but not in the muscles, Jackson et al., Clin. Chim. Acta 196, (1991) 193-206; and Lenney et al., Biochem. J. 228 (1985) 653-660 and probably, the lens, Boldyrev et al., “The antioxidative properties of carnosine, a natural histidine containing dipeptide,” Biochem Int (1987) 15: 1105-1113; Jay et al., “Histidyl derivatives in rabbit lens and their diminution in human cataract,” Meeting Abstr J Physiol Lond (1990) 420:155.
PCT/EP94/03340 discloses that N-acetylcarnosine is a prodrug for L-carnosine, and proposes a topical medicant containing N-acetylcarnosine useful in the prevention and therapy of cataract. See also Babizhayev et al., “N-Acetylcarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant,” Clin Chim Acta (1996) 254: 1-21; Babizhayev et al., “The natural histidine-containing dipeptide N-acetylcarnosine as an antioxidant for ophthalmic use, Biochemistry (Moscow) (2000), 65/5: 588-598; Babizhayev et al., “Efficacy of N-acetylcarnosine in the treatment of cataracts, Drugs R&D (2002), 3(2):87-103; Babizhayev et al., “N-acetylcarnosine, a natural histidine-containing dipeptide, as a potent ophthalmic drug in treatment of human cataracts, Peptides (2001) 22(6): 979-994; and Babizhayev et al., “Imidazole-containing peptidomimetic NACA as a potent drug for the medicinal treatment of age-related cataract in humans,” J Anti-Aging Medicine (2000) 3/1: 43-62.
U.S. Pat. No. 4,387,232 discloses a process for preparing N-acetyl-β-alanyl-L-histidine, which is said to possess a strong controlling action to the cerebrum surroundings. The process reacts histidine and 3-acylaminopropionic acid reactive derivatives such as 3-acetylaminopropionic chloride, and the tertiary amine salt of 3-acetylaminopropionic acid and sulfuric acid mixed anhydride.
U.S. Pat. No. 5,866,537 discloses an oral composition containing the combination of carnosine and branched amino acids leucine, isoleucine and valine. The composition is said to induce a prolonged antioxidant activity in comparison to carnosine alone. Carnosine derivatives such as homocarnosine, acetylcarnosine, anserine, acetylanserine and ofidine, and/or their biologically acceptable inorganic and organic salts, and/or acyl derivatives may be used in place of carnosine.
Carboxymethylcellulose sodium salt is widely used in oral and topical pharmaceutical formulations primarily for its viscosity-increasing properties. Viscous aqueous solutions are used to suspend powders intended for either topical application or oral and parenteral administration. See Hussain et al., “Injectable suspensions for prolonged release nalbuphine,” Drug Dev Ind Pharm (1991), 17: 67-76. Carboxymethylcellulose sodium may also be used as a tablet binder and disintegrant, Khan K A et al., “Evaluation of different viscosity grades of sodium carboxymethylcellulose as tablet disintegrants,” Pharm Acta Helv (1975), 50: 99-102, and to stabilize emulsions, Oza et al., “Microcrystalline cellulose stabilized emulsions,” J Disper Sci Technol (1986), 7(5): 543-561. Higher concentrations, usually 3-6%, of the medium viscosity grade is used to produce gels which can be used as the base for pastes. Carboxymethylcellulose sodium salt is additionally one of the main ingredients of self-adhesive ostomy, wound care, and dermatological patches where it is used to absorb wound exudates or transepidermal water and sweat. Carboxymethylcellulose sodium salt is also used in cosmetics, toiletries, incontinence, personal hygiene, and food products. See Mombellet et al., “Sodium carboxymethylcellulose toothpaste,” Mfg Chem 1088; 59(11): 47,49, and 52.
U.S. Pat. No. 6,194,457 discloses the use of lubricants such as sodium carboxymethylcellulose in a liquid eye drop composition which contains reduced glutathione, vitamin A and vitamin E, as well as one or more of zinc sulfate, boric acid and potassium as buffering agents. The composition also may contain a preservative such as benzyl alcohol. The composition is used in a method of treating eyes for the alleviation of irritations and/or dryness, as well as for the prevention and treatment of cataracts.
N-acetylcarnosine per se can act as a very weak antioxidant and vitamin A and its derivatives can possess pro-oxidant action via superoxide generation, Murata et al., “Oxidative DNA damage by vitamin A and its derivative via superoxide generation” J Biol Chem (2000); 275:2003-8. Besides, the vitamin E molecule with branched hydrocarbon skeleton completely inhibits the deacetylation of the amino acid derivative product, Teixeira et al., “Use of antioxidants for the prophylaxis of cold-induced peripheral nerve injury,” Mil Med (2002); 167:753-5 and reduced glutathione promotes the formation of posterior subcapsular cataracts when applied in the ophthalmic compositions, Sharma et al. “Topical glutathione therapy in senile cataracts. Cataract-III.” Indian J Opthalmol (1989); 37(3):121-6.
An object of the present invention is to provide an ophthalmic composition containing N-acetylcarnosine which is safe and which is completely converted into L-carnosine in the aqueous humor.
Another object of the invention is to provide an ophthalmic composition which can significantly increase the bioavailability of N-acetylcarnosine/L-carnosine in the aqueous humor.